pulmonary hypertension
by subbia1988
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1. pulmonary hypertension

Disclaimer: Not mine.. no money made.. don't sue me..

PULMONARY HYPERTENSION - Stuart Rich

INTRODUCTION

Pulmonary hypertension, an abnormal elevation in pulmonary artery pressure, may reflect an increase in left heart filling pressure in the presence of normal pulmonary vascular resistance, pulmonary vascular or parenchymal disease with an elevation in pulmonary vascular resistance, or a combination of these initiating factors. Whether the pulmonary hypertension arises from cardiac, pulmonary, or intrinsic vascular disease, it generally is a feature of advanced disease. Because the causes of pulmonary hypertension are so diverse, it is essential that the etiology underlying the pulmonary hypertension be clearly determined before embarking on treatment. Recent data suggest that mild increases in pulmonary artery pressure also occur with age as the pulmonary circulation becomes less compliant.

Cor pulmonale (Chap. 216) is a term used to indicate right ventricular (RV) enlargement secondary to any underlying cardiac or pulmonary disease. Pulmonary hypertension is the most common cause of cor pulmonale. Advanced cor pulmonale is associated with the development of RV failure.

PATHOPHYSIOLOGY

The right ventricle responds to an increase in resistance within the pulmonary circulation by increasing RV systolic pressure as necessary to preserve cardiac output. The increase in pulmonary vascular resistance may be attributed to excessive production of vascular growth factors, mechanical obstruction of the pulmonary arteries, hypoxia, or other stimuli. Over time, chronic changes occur in the pulmonary circulation resulting in remodeling of the vasculature, which can sustain or promote pulmonary hypertension even if the initiating factor is removed.

On occasion a patient may have marked elevations in pulmonary artery pressure in association with obstructive or interstitial lung disease, essential hypertension, ischemic heart disease, or valvular heart disease. Although it may appear that the pulmonary hypertension is out of proportion to the underlying associated condition, it likely represents a pulmonary vasoconstrictor response to the associated condition, which serves as a trigger of the pulmonary arteriopathy. The distinction is important because the treatment of pulmonary hypertension should include treating the underlying associated cause whenever possible.

The ability of the right ventricle to adapt to increased vascular resistance is influenced by several factors including age and the rapidity of the development of pulmonary hypertension. For example, a large acute pulmonary thromboembolism can result in RV failure and shock, whereas chronic thromboembolic disease of equal severity may result in only mild exercise intolerance. Coexisting hypoxemia from lung disease or myocardial ischemia from coronary artery disease can impair the ability of the ventricle to compensate. The onset of clinical RV failure, usually manifest by peripheral edema, is associated with a poor outcome.

DIAGNOSIS

A thorough diagnostic evaluation of all potential causes of pulmonary hypertension should be undertaken (Fig. 220-1). The most common symptom attributable to pulmonary hypertension is exertional dyspnea. Other common symptoms are fatigue, angina pectoris that may represent RV ischemia, syncope, near syncope, and peripheral edema.

The physical examination typically reveals increased jugular venous pressure, a reduced carotid pulse, and a palpable RV lift. Most patients have an increased pulmonic component of the second heart sound and a right-sided fourth heart sound (Chap. 209). Tricuspid regurgitation is a clinical feature of RV failure. Peripheral cyanosis and/or edema tend to occur in later stages of the disease. The presence of clubbing can be a clinical clue that the patient has underlying congenital heart disease or hypoxemic lung disease.

Laboratory Findings The chest x-ray generally shows enlarged central pulmonary arteries. The lung fields may or may not reveal other pathology. The electrocardiogram usually reveals right axis deviation and RV hypertrophy. The echocardiogram commonly demonstrates RV and right atrial enlargement, a reduction in left ventricular (LV) cavity size, and a tricuspid regurgitant jet that can be used to estimate RV systolic pressure. Pulmonary function tests are helpful in documenting underlying obstructive airways disease or severe restrictive lung disease. Hypoxemia and an abnormal diffusing capacity for carbon monoxide are common findings of pulmonary hypertension of most causes. A perfusion lung scan is almost always abnormal in patients with thromboembolic pulmonary hypertension (Chap. 244). However, diffuse patchy filling defects of a nonsegmental nature can often be seen in longstanding pulmonary hypertension in the absence of thromboemboli. Laboratory tests should also be performed, including antinuclear antibody and HIV1 testing. Because of the high frequency of thyroid abnormalities in patients with primary pulmonary hypertension, it is recommended that the thyroid-stimulating hormone level be determined as well.

Cardiac Catheterization This procedure is mandatory for accurate measurement of pulmonary artery pressure, cardiac output, and LV filling pressure, as well as for exclusion of an underlying cardiac shunt. Because of the difficulty in obtaining accurate pulmonary capillary wedge pressures in patients with pulmonary vascular disease, it is desirable to perform a left heart catheterization to identify an elevation of LV end-diastolic pressure as the cause of the pulmonary hypertension. It is also recommended that patients with pulmonary arterial hypertension undergo drug testing with a short-acting pulmonary vasodilator at the time of cardiac catheterization to determine the extent of pulmonary vasodilator reactivity (Fig. 220-2). Inhaled nitric oxide, intravenous adenosine, and intravenous epoprostenol appear to have similar effects in reducing pulmonary artery pressure acutely with little effect on the systemic vascular bed. Nitric oxide is generally administered via inhalation in 10 to 20 parts per million. Adenosine is given as an infusion of doses of 50 ug/kg per min and increased every 2 min until side effects develop. Epoprostenol is given in doses of 2 ng/kg per min and increased every 30 min until side effects develop. Maximal physiologic effectiveness of the drug is determined at the highest tolerated dose. Patients who respond can usually be treated with calcium channel blockers and have a more favorable prognosis.

It is a misperception that the preferred treatment of pulmonary hypertension from any cause is vasodilators, which is the common approach to treating essential hypertension. While vasodilators may benefit selected patients, successful therapies of pulmonary hypertension include those that improve RV function, normalize cardiac output, and improve oxygenation in addition to therapies directed toward inhibiting the vasoproliferative process in the pulmonary vascular bed.

PULMONARY ARTERIAL HYPERTENSION

The causes of pulmonary arterial hypertension (Table 220-1) include primary pulmonary hypertension, pulmonary hypertension associated with the collagen vascular diseases, congenital systemic to pulmonary shunts, portal hypertension, HIV infection, anorexigen use, and persistent pulmonary hypertension of the newborn. These patients share a common histopathology that includes pulmonary vascular abnormalities involving the endothelium, smooth-muscle cells, and extracellular matrix. The most common features are medial hypertrophy, eccentric and concentric intimal fibrosis, recanalized thrombi appearing as fibrous webs, and plexiform lesions.

Pathobiology There are likely several pathobiologic processes that result in pulmonary arterial hypertension as a final common pathway. These include inhibition of the voltage-regulated potassium channel producing vasoconstriction of the pulmonary artery smooth-muscle cells, reduced expression of nitric oxide synthase in the endothelium of the pulmonary arterial bed, increased expression of endothelin and basic fibroblast growth factor, and thrombin deposition related to a procoagulant state. The types of abnormalities that occur are likely influenced by the patient's genotype and exposure to risk factors that serve to trigger these processes.

PRIMARY PULMONARY HYPERTENSION

Primary pulmonary hypertension (PPH) is uncommon, with an estimated incidence of 2 cases per million. There is a strong female predominance, with most patients presenting in the fourth and fifth decades, although the age range is from infancy to 60 years.

GENETIC CONSIDERATIONS

Familial PPH2 accounts for 12 to 20% of cases of PPH and is characterized by autosomal dominant inheritance, variable age of onset, and incomplete penetrance. The clinical and pathologic features of familial and sporadic PPH are identical. Heterozygous germline mutations that involve the gene coding the type II bone morphogenetic protein receptor (BMPR II), a member of the transforming growth factor ß superfamily, have been found to underly many cases of familial PPH. This gene, which is located on chromosome 2q31, has been designated as the PPH I gene. An interruption in the BMP-mediated signaling pathway predisposes the cells within the small pulmonary arteries to proliferation rather than apoptosis. These observations support the concept that PPH is a result of abnormal proliferation of pulmonary vascular endothelial and smooth-muscle cells.

NATURAL HISTORY

The natural history of PPH3 is uncertain because initially the disease can be asymptomatic. Because the predominant symptom is dyspnea, which can have an insidious onset, the disease is typically diagnosed late in its course. Prior to current therapies, a mean survival of 2 to 3 years from the time of diagnosis was reported. It appears that the survival of patients with pulmonary hypertension secondary to congenital heart disease is longer than for patients with PPH, while the survival of patients with pulmonary hypertension secondary to scleroderma is shorter. Functional class remains a strong predictor of survival, with patients who are in New York Heart Association (NYHA) functional class IV having a mean survival of 6 months. The cause of death is usually RV failure, which is manifest by progressive hypoxemia, tachycardia, hypotension, and edema.

TREATMENT

Because the pulmonary artery pressure in PPH4 increases dramatically with exercise, patients should be cautioned against participating in activities that demand increased physical stress. Digoxin may increase cardiac output and lower circulating levels of norepinephrine. Diuretic therapy relieves peripheral edema and may be useful in reducing RV volume overload in the presence of tricuspid regurgitation. Resting and exercise pulse oximetry should be obtained, as oxygen supplementation helps to alleviate dyspnea and RV ischemia in patients whose arterial oxygen saturation is reduced. Anticoagulant therapy is advocated for all patients with PPH since thrombin deposition occurs in the pulmonary circulation; thrombin can serve as a growth factor to promote the disease process. One retrospective study and one prospective study demonstrated that the anticoagulant warfarin increases survival of patients with PPH. The dose of warfarin is generally titrated to achieve an INR of two to three times control.

Calcium Channel Blockers Patients who have substantial reductions in pulmonary arterial pressure in response to short-acting vasodilators at the time of cardiac catheterization may be candidates for oral calcium channel blockers. Typically, patients require high doses (e.g., nifedipine, 240 mg/d, or amlodipine, 20 mg/d1). Patients who respond favorably usually have dramatic reductions in pulmonary artery pressure and pulmonary vascular resistance associated with improved symptoms, regression of RV hypertrophy, and improved survival with chronic therapy. However, 20% of patients respond to calcium channel blockers in the long term. These drugs can be particularly hazardous when given to patients who are unresponsive, as they can result in hypotension, hypoxemia, tachycardia, and worsening right heart failure.

1 These agents have not been approved for the treatment of primary pulmonary hypertension by the U.S. Food and Drug Administration.

Prostacyclins Epoprostenol is the best characterized approved treatment of pulmonary arterial hypertension for patients who are NYHA5 functional class III or IV and unresponsive to other therapies. Clinical trials have demonstrated an improvement in symptoms, exercise tolerance, and survival even if no acute hemodynamic response to drug challenge occurs. Recent reports have documented sustained benefits for 10 years in some patients. The drug can only be administered intravenously and requires placement of a permanent central venous catheter and infusion through an ambulatory infusion pump system. It generally takes several months to titrate the dose gradually upwards to optimal clinical efficacy, which is usually between 25 and 50 ng/kg per min. Side effects include flushing, jaw pain, and diarrhea, which are generally tolerated by most patients. The major problem with this therapy is infection related to the venous catheter, which requires close monitoring and diligence on behalf of the patient.

Recently, treprostinil has been approved for patients with PPH6 who are NYHA7 functional classes II to IV and who are unresponsive to conventional therapy, defined as anticoagulation, diuretics, and calcium blockers. An analogue of epoprostenol, treprostinil has a longer half-life and is stable at room temperature, allowing it to be administered subcutaneously through a small infusion pump that was originally developed for insulin. Short-term clinical trials have demonstrated an increase in exercise capacity and a reduction of dyspnea. The major problem with this treatment has been local pain at the infusion site, which has caused patients to discontinue therapy.

Endothelin Receptor Antagonists The nonselective endothelin receptor antagonist bosentan was recently approved as an oral treatment of PPH8 for patients who are NYHA9 functional classes III and IV and who are unresponsive to conventional therapy. In randomized clinical trials, bosentan was shown to improve exercise tolerance as measured by an increase in 6-min walk distance, improve functional class, and extend time until clinical worsening versus placebo. Therapy is initiated at 62.5 mg bid for the first month and then increased to 125 mg bid thereafter. Because of the high frequency of abnormal hepatic function tests associated with drug use, primarily an increase in transaminases, it is recommended that liver function be monitored monthly throughout the duration of use. Bosentan is also contraindicated in patients who are currently on cyclosporine or glyburide. There are no data to support the use of bosentan for other forms of pulmonary hypertension.

Sildenafil There have been several case reports on the use of sildenafil (Viagra), an oral phosphodiesterase-5 inhibitor, in the treatment of pulmonary hypertension. Phosphodiesterase-5 is responsible for the hydrolysis of cyclic GMP in pulmonary vascular smooth muscles, the mediator through which nitric oxide lowers pulmonary artery pressure and inhibits pulmonary vascular growth. These reports suggest that oral sildenafil has a similar efficacy to inhaled nitric oxide. Large randomized clinical trials using sildenafil as a treatment of pulmonary hypertension are under consideration.

Lung Transplantation (See also Chap. 248) Lung transplantation is considered for patients who, while on epoprostenol, continue to manifest right heart failure. Acceptable results have been achieved with heart-lung, bilateral lung, and single lung transplant. The availability of donor organs often influences the choice of procedure. The recurrence of PPH10 has never been reported in a patient who has undergone lung transplantation.

CONDITIONS ASSOCIATED WITH PULMONARY HYPERTENSION

COLLAGEN VASCULAR DISEASE

All of the collagen vascular diseases may be associated with pulmonary arterial hypertension. This complication occurs commonly with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal involvement, sclerodactyly, and telangiectasia) and in scleroderma (Chap. 303), and less frequently in systemic lupus erythematosus (Chap. 300), Sjogrens syndrome (Chap. 304), dermatomyositis, polymyositis (Chap. 306), and rheumatoid arthritis (Chap. 301). It is usual for these patients to have some element of coexistent interstitial pulmonary fibrosis even though it may not be apparent on chest x-ray, computed tomography, or pulmonary function tests. Consequently, these patients tend to have hypoxemia as an important clinical feature, along with the other classic findings of pulmonary hypertension.

Treatment for these patients is identical to that for patients with PPH11 (see above) but is less effective. It is rare for these patients to respond to calcium channel blockers. Bosentan, treprostinil, and epoprostenol have been effective in clinical trials. The treatment of the pulmonary hypertension, however, does not affect the natural history of the underlying collagen vascular disease.

CONGENITAL SYSTEMIC TO PULMONARY SHUNTS

It is common for large post-tricuspid cardiac shunts (e.g., ventricular septal defect, patent ductus arteriosus) to produce severe pulmonary hypertension (Chap. 218), which, although less common, may also occur in pre-tricuspid shunts (e.g., atrial septal defect, anomalous pulmonary venous drainage). In patients with uncorrected shunts, the clinical features include those associated with right-to-left shunting such as hypoxemia and peripheral cyanosis, which worsen dramatically with exertion (Chap. 31). Pulmonary arterial hypertension may occur years or even decades after surgical correction of these lesions, in which case there will be no associated right-to-left shunting. These patients present similarly to patients with PPH12 but tend to have better long-term survival. This has been attributed to the more slowly progressive nature of the underlying vascular disease. The treatments are similar to those for PPH.

PORTAL HYPERTENSION

Portal hypertension is associated with pulmonary arterial hypertension, but the mechanism remains unknown. The risk is not related to the severity of underlying liver disease. Patients with advanced cirrhosis can have the combined features of a high-output cardiac state in association with the features of pulmonary hypertension and RV failure. Thus, a normal cardiac output may actually reflect a marked impairment of RV function. The etiology of ascites and edema can be confusing in these patients since it can have both cardiac and hepatic causes. Venous congestion from right heart failure, however, is poorly tolerated by cirrhotic livers. Patients with mild pulmonary hypertension who have a favorable response to epoprostenol have undergone successful liver transplantation with improvement of the pulmonary vascular disease.

HIV INFECTION

The mechanism by which HIV1 infection produces pulmonary hypertension remains unknown (Chap. 173). The evaluation and treatment are identical to those for PPH13. Treatment of the HIV infection does not appear to affect the severity or natural history of the underlying pulmonary hypertension.

ANOREXIGENS

A causal relationship has been established between exposure to several anorexigens, including aminorex and the fenfluramines, and the development of pulmonary arterial hypertension. Although the fenfluramines were removed from the world markets in 1997, there are still patients who were exposed prior to that time who are now developing pulmonary hypertension. While the clinical features are identical to those of PPH14, the patients appear to be less responsive to medical treatments and have a poorer prognosis.

PULMONARY VENOOCCLUSIVE DISEASE

Pulmonary venoocclusive disease is a rare and distinct pathologic entity found in 10% of patients who present with the diagnosis of unexplained pulmonary hypertension. Histologically it is manifest by widespread intimal proliferation and fibrosis of the intrapulmonary veins and venules, occasionally extending to the arteriolar bed. The pulmonary venous obstruction explains the increase in pulmonary capillary wedge pressure observed in patients with advanced disease. These patients may develop orthopnea that can mimic LV failure. The therapy of this condition is not established.

PULMONARY CAPILLARY HEMANGIOMATOSIS

Pulmonary capillary hemangiomatosis is a very rare form of pulmonary hypertension. Histologically it is characterized by the presence of infiltrating thin-walled blood vessels throughout the pulmonary interstitium and walls of the pulmonary arteries and veins. The presenting symptoms are usually those of PPH15 but often with hemoptysis as a clinical feature. The diagnosis can be made with pulmonary angiography. The clinical course is usually one of progressive deterioration leading to severe pulmonary hypertension, right-sided heart failure, and death. There is no established therapy.

PULMONARY VENOUS HYPERTENSION

Pulmonary hypertension occurs as a result of increased resistance to pulmonary venous drainage. It is often associated with diastolic dysfunction of the left ventricle; diseases affecting the pericardium or mitral or aortic valves; or rare entities such as cor triatriatum, left atrial myxoma, extrinsic compression of the central pulmonary veins from fibrosing mediastinitis, and pulmonary venoocclusive disease. Pulmonary venous hypertension affects the pulmonary veins and venules, producing arterialization of the external elastic lamina, medial hypertrophy, and focal eccentric intimal fibrosis. Microcirculatory lesions include capillary congestion, focal alveolar edema, and dilatation of the interstitial lymphatics. Although these lesions are potentially reversible, regression may take years after the underlying cause is removed. In some patients pulmonary venous hypertension triggers reactive vasoconstriction in the pulmonary arterial bed and results in proliferative changes of the intima and media that can produce severe elevations in pulmonary artery pressure. Clinically it may be confusing and appear as if two separate disease processes are occurring simultaneously.

LEFT VENTRICULAR DIASTOLIC DYSFUNCTION

Pulmonary hypertension as a result of LV diastolic failure is common but often unrecognized (Chap. 216). It can occur with or without LV systolic failure. The most common causes are hypertensive heart disease; coronary artery disease; or impaired LV compliance related to age, diabetes, and hypoxemia. Symptoms of orthopnea and paroxysmal nocturnal dyspnea are prominent. Many patients improve considerably if LV end-diastolic pressure is lowered.

MITRAL VALVE DISEASE

Mitral stenosis and mitral regurgitation represent important causes of pulmonary hypertension (Chap. 219). These patients often have superimposed pulmonary vasoconstriction resulting in marked elevations in pulmonary artery pressures. An echocardiogram usually shows abnormalities such as thickened mitral valve leaflets with reduced mobility or severe mitral regurgitation documented by Doppler echocardiography (Chap. 211). At cardiac catheterization a pressure gradient between the pulmonary capillary wedge pressure and LV end-diastolic pressure is diagnostic of mitral stenosis.

In patients with mitral stenosis corrective surgery of the mitral valve or mitral balloon valvuloplasty predictably results in a reduction in pulmonary artery pressure and pulmonary vascular resistance. Patients with mitral regurgitation, however, may not have as dramatic a response from surgery due to persistent elevations in LV end-diastolic pressure.

PULMONARY HYPERTENSION ASSOCIATED WITH LUNG DISEASE AND HYPOXEMIA

The mechanism of hypoxic pulmonary vasoconstriction involves the inhibition of potassium currents and membrane depolarization of pulmonary vascular smooth muscle as a result of the change in membrane sulfhydryl redox status. Increased calcium entry into the vascular smooth-muscle cells mediates hypoxic pulmonary vasoconstriction. Pulmonary vascular remodeling in response to chronic hypoxia is also mediated by a reduction in nitric oxide production; an increase in endothelin 1; and increased expression of platelet-derived growth factors, vascular endothelial growth factor, and angiotensin II. Chronic hypoxia results in muscularization of the arterioles with minimal effects on the intima. When it occurs as an isolated entity, the changes produced are potentially reversible.

Although chronic hypoxia is an established cause of pulmonary hypertension, it rarely leads to an increase in the mean pulmonary artery pressure 40 mmHg. Polycythemia in response to the hypoxemia is a characteristic finding. Hypoxia may also occur in conjunction with other causes of pulmonary hypertension associated with more extensive vascular changes. Clinically, the hypoxia will tend to have an added adverse affect. Patients with chronic hypoxia who have a marked elevation in pulmonary pressure should be evaluated for other causes of the pulmonary hypertension.

CHRONIC OBSTRUCTIVE LUNG DISEASE

Chronic obstructive lung disease (COLD) is a common cause of pulmonary hypertension in the advanced stages (Chap. 242). Pulmonary hypertension has been attributed to multiple factors, including hypoxic pulmonary vasoconstriction, acidemia, hypercapnia, the mechanical effects of high lung volume on pulmonary vessels, the loss of small vessels in the vascular bed, and regions of emphysematous lung destruction.

Although the elevation of pulmonary artery pressure associated with COLD16 tends to be mild, the presence of pulmonary hypertension confers a worse outcome. The only effective therapy is supplemental oxygen. Several large clinical trials have documented that continuous oxygen therapy relieves some of the pulmonary vasoconstriction, relieves chronic ischemia throughout the systemic and pulmonary vascular beds, and improves survival. Long-term oxygen therapy is indicated if the resting arterial PO2 remains 55 mmHg.

INTERSTITIAL LUNG DISEASE

Pulmonary hypertension from interstitial lung disease is often associated with obliteration of the pulmonary vascular bed by lung destruction and fibrosis (Chap. 243). In addition, hypoxemia and pulmonary vasculopathy can be contributory factors. A large number of patients have pulmonary fibrosis of unknown etiology. Interstitial lung disease is often associated with the collagen vascular diseases. Patients are commonly older than 50 years and report an insidious onset of progressive dyspnea and cough for months to years. A definitive diagnosis requires an open-lung biopsy to rule out other diseases such as bronchiolitis obliterans, nonspecific interstitial pneumonia, and hypersensitivity pneumonitis. Management of these disorders is discussed in Chap. 243. None of the medical treatments developed for pulmonary arterial hypertension have been shown to be effective in these patients.

SLEEP-DISORDERED BREATHING

Sleep apnea, defined as repeated episodes of obstructive apnea and hypopnea during sleep together with daytime somnolence and altered cardiopulmonary function, is a common condition (Chap. 247). The incidence of pulmonary hypertension in the setting of obstructive sleep apnea appears to be 20% and is generally mild. Therapeutic strategies for patients with sleep apnea should be directed towards establishing normal nocturnal oxygenation and ventilation, abolishing snoring, eliminating disruption of sleep due to upper airway closure, and avoiding factors that tend to aggravate the condition such as alcohol, sedatives, and hypnotic agents. The most important advance in medical treatment has been positive airway pressure delivered through a face mask during sleep.

When mild pulmonary hypertension is associated with sleep apnea, the treatments directed towards the sleep apnea are often effective in reducing pulmonary arterial pressure. Some patients, however, will present with severe pulmonary hypertension in conjunction with sleep apnea, which may or may not be related. In these cases it is recommended that the patients be treated for sleep apnea for a minimum of 3 months before treating the pulmonary arterial hypertension as a separate entity.

ALVEOLAR HYPOVENTILATION

Pulmonary hypertension can occur in patients with chronic hypoventilation and hypoxia secondary to thoracovertebral deformities. Symptoms are slowly progressive and related to hypoxemia (Chap. 246). In patients with advanced disease, intermittent positive-pressure breathing and supplemental oxygen have been used successfully.

Pulmonary hypertension secondary to hypoxemia has been reported in patients with neuromuscular disease as a result of generalized weakness of the respiratory muscles and in patients with diaphragmatic paralysis. Diaphragmatic paralysis is generally a result of trauma to the phrenic nerve. Patients with nontraumatic bilateral diaphragmatic paralysis may go unrecognized until they present with either respiratory failure or pulmonary hypertension.

PULMONARY HYPERTENSION DUE TO THROMBOEMBOLIC DISEASE

ACUTE PULMONARY THROMBOEMBOLISM SEE CHAP. 2

CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION

Patients appropriately treated for acute pulmonary thromboembolism with intravenous heparin and chronic oral warfarin therapy rarely develop chronic pulmonary hypertension. However, there is a subset of patients with impaired fibrinolytic resolution of the thromboembolism, which leads to organization and incomplete recanalization and chronic obstruction of the pulmonary vascular bed. The entity of chronic thromboembolic pulmonary hypertension has been well characterized and often mimics PPH17. In many patients, the initial pulmonary thromboembolism was undetected or untreated.

Diagnosis The physical examination is typical of pulmonary hypertension but may include bruits heard over areas of the lung, representing blood flow through vessels with partial occlusion. A perfusion lung scan or contrast-enhanced spiral computed tomography scan usually reveals underlying thromboemboli. However, pulmonary angiography is necessary to determine the precise location and proximal extent of the thromboemboli, and hence the potential for operability.

TREATMENT

Pulmonary thromboendarterectomy is an established surgical treatment in patients whose thrombi are accessible to surgical removal. The operative mortality is fairly high, at ~12% in experienced centers. Postoperative survivors who have a good result can expect to realize an improvement in functional class and exercise tolerance. Life-long anticoagulation using warfarin is mandatory. Thrombolytic therapy is rarely of help in patients with chronic thromboembolic pulmonary hypertension and may expose these patients to the increased risk of bleeding without potential benefit. Patients who are not surgical candidates have a poor outcome.

SICKLE CELL DISEASE

Cardiovascular system abnormalities are prominent in the clinical spectrum of sickle cell disease, and pulmonary hypertension has been reported to occur in 20% of patients (Chap. 91). The pulmonary hypertension can usually be attributed to LV diastolic dysfunction. Although patients with sickle cell disease have an increased risk of thromboembolism, sickle cell disease rarely produces pulmonary arterial hypertension.

OTHER DISORDERS DIRECTLY AFFECTING PULMONARY VASCULATURE

SARCOIDOSIS

Sarcoidosis can produce severe pulmonary hypertension as a result of chronic severe fibrocystic lung involvement (Chap. 309). In addition, direct cardiovascular involvement can coexist. Consequently, patients with sarcoidosis who present with progressive dyspnea and clinical features of pulmonary hypertension need a thorough evaluation. There is a subset of patients with sarcoidosis who present with severe pulmonary hypertension believed to be due to direct pulmonary vascular involvement. Many of these patients exhibit a favorable response to intravenous epoprostenol therapy.

SCHISTOSOMIASIS

Although extremely rare in North America, schistosomiasis is the most common cause of pulmonary hypertension worldwide (Chap. 203). The development of pulmonary hypertension almost always occurs in the setting of hepatosplenic disease and portal hypertension. Schistosome ova can embolize from the liver to the lungs, where they result in an inflammatory pulmonary vascular reaction and chronic changes. The diagnosis is confirmed by finding the parasite ova in the urine or stools of patients with symptoms, which can be difficult. The efficacy of therapies directed towards pulmonary hypertension in these patients is unknown.


	2. pulm thromboembolism

Disclaimer: Not mine.. no money made.. don't sue me..

PULMONARY THROMBOEMBOLISM - Samuel Z. Goldhaber

PREDISPOSITION TO PULMONARY THROMBOEMBOLISM

Acquired and genetic factors contribute to the likelihood of venous thromboembolism. Acquired predispositions include long-haul air travel, obesity, cigarette smoking, oral contraceptives, pregnancy, postmenopausal hormone replacement, surgery, trauma, and medical conditions such as antiphospholipid antibody syndrome, cancer, systemic arterial hypertension, and chronic obstructive pulmonary disease. Thrombophilia contributes greatly to the risk of venous thrombosis, often due to an inherited risk factor in combination with an acquired predisposition. The two most common autosomal dominant genetic mutations are the factor V Leiden and the prothrombin gene mutations (Chap. 56). Only a minority of patients with venous thromboembolism has identifiable predisposing genetic factors. Some patients with predisposing genetic factors will never develop clinical evidence of clotting.

PATHOPHYSIOLOGY

EMBOLIZATION

When venous thrombi dislodge from their site of formation, they embolize to the pulmonary arterial circulation or, paradoxically, to the arterial circulation through a patent foramen ovale or atrial septal defect. About half of patients with pelvic vein thrombosis or proximal leg deep venous thrombosis (DVT) have pulmonary thromboembolism (PE), which is usually asymptomatic. Isolated calf vein thrombi pose a lower risk of PE, but they are the most common source of paradoxical embolism. With increased use of chronic indwelling central venous catheters for hyperalimentation and chemotherapy, as well as more frequent insertion of permanent pacemakers and internal cardiac defibrillators, upper extremity venous thrombosis is becoming a more common problem. These thrombi may also embolize and cause PE.

PHYSIOLOGY

Pulmonary embolism can have the following effects:

1. Increased pulmonary vascular resistance due to vascular obstruction or platelet secretion of neurohumoral agents including serotonin

2. Impaired gas exchange due to increased alveolar dead space from vascular obstruction, hypoxemia from alveolar hypoventilation relative to perfusion in the nonobstructed lung, right-to-left shunting, and impaired carbon monoxide transfer due to loss of gas exchange surface

3. Alveolar hyperventilation due to reflex stimulation of irritant receptors

4. Increased airway resistance due to constriction of airways distal to the bronchi

5. Decreased pulmonary compliance due to lung edema, lung hemorrhage, or loss of surfactant

Right Ventricular Dysfunction Progressive right heart failure is the usual cause of death from PE1. In the International Cooperative Pulmonary Embolism Registry (ICOPER), the presence of right ventricular dysfunction on baseline echocardiography of PE patients was associated with a doubling of the 3-month mortality rate. As pulmonary vascular resistance increases, right ventricular wall tension rises and perpetuates further right ventricular dilatation and dysfunction. Consequently, the interventricular septum bulges into and compresses an intrinsically normal left ventricle. Increased right ventricular wall tension also compresses the right coronary artery and may precipitate myocardial ischemia and right ventricular infarction. Underfilling of the left ventricle may lead to a fall in left ventricular output and systemic arterial pressure, thereby provoking myocardial ischemia due to compromised coronary artery perfusion. Eventually, circulatory collapse and death may ensue.

DIAGNOSIS

The clinical setting, including risk factors such as family history or personal prior history of venous thromboembolism, can help suggest the diagnosis of PE1. Semi-quantitative clinical scoring systems such as the Wells Diagnostic Scoring System are beginning to replace "gestalt" estimates of clinical likelihood (Table 244-1).

CLINICAL SYNDROMES

Patients with massive PE1 present with systemic arterial hypotension and usually have anatomically widespread thromboembolism. Primary therapy with thrombolysis or embolectomy offers the greatest chance of survival. Those with moderate to large PE have right ventricular hypokinesis on echocardiography but normal systemic arterial pressure. Optimal management is controversial; such patients may benefit from thrombolysis or embolectomy rather than anticoagulation alone. Patients with small to moderate PE have both normal right heart function and normal systemic arterial pressure. They have a good prognosis with either adequate anticoagulation. The presence of pulmonary infarction usually indicates a small PE, but one that is exquisitely painful, because it lodges peripherally, near the innervation of pleural nerves. However, larger, more central PEs can occur concomitantly with peripheral pulmonary infarction.

Nonthrombotic pulmonary embolism may be easily overlooked. Possible etiologies include fat embolism after blunt trauma and long bone fractures, tumor embolism, or air embolism. Intravenous drug users may inject themselves with a wide array of substances, such as hair, talc, or cotton. Amniotic fluid embolism occurs when fetal membranes leak or tear at the placental margin. The pulmonary edema seen in this syndrome is probably due primarily to alveolar capillary leakage.

SYMPTOMS AND SIGNS

Dyspnea is the most frequent symptom of PE1, and tachypnea is its most frequent sign. Whereas dyspnea, syncope, hypotension, or cyanosis indicates a massive PE, pleuritic pain, cough, or hemoptysis often suggests a small embolism located distally near the pleura. On physical examination, young and previously healthy individuals may simply appear anxious but otherwise seem deceptively well, even with an anatomically large PE. They may only have dyspnea with moderate exertion. They often lack "classic" signs such as tachycardia, low-grade fever, neck vein distention, or an accentuated pulmonic component of the second heart sound. Sometimes, a paradoxical bradycardia occurs.

In older patients who complain of vague chest discomfort, the diagnosis of PE1 may not be apparent unless signs of right heart failure are present. Unfortunately, because acute coronary ischemic syndromes are so common, one may overlook the possibility of life-threatening PE and may inadvertently discharge these patients from the hospital after the exclusion of myocardial infarction with serial blood tests to detect cardiac injury and serial electrocardiograms.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of PE1 is broad (Table 244-2). Although PE is known as "the great masquerader," quite often other illnesses simulate PE. For example, when the proposed diagnosis of PE is supposedly confirmed with a combination of dyspnea, chest pain, and an abnormal lung scan, the correct diagnosis of pneumonia might become apparent 12 h later when an infiltrate blossoms on chest x-ray, purulent sputum is first produced, and high fever and shaking chills develop.

Some patients have PE1 and a coexisting illness such as pneumonia or heart failure. In such circumstances, clinical improvement will often fail to occur despite standard medical treatment of the concomitant illness. This situation can serve as a clinical clue to the possible coexistence of PE.

NONIMAGING DIAGNOSTIC MODALITIES

These are generally less expensive but also less specific than diagnostic modalities that employ imaging.

Blood Tests The quantitative plasma D-dimer enzyme-linked immunosorbent assay (ELISA) level is elevated (500 ng/mL) in more than 90% of patients with PE1, reflecting plasmin's breakdown of fibrin and indicating endogenous (though clinically ineffective) thrombolysis. However, the D-dimer assay is not specific and therefore has no useful role among patients who are already hospitalized. Levels increase in patients with myocardial infarction, sepsis, or almost any systemic illness. The plasma D-dimer ELISA has a high negative predictive value and can be used to help exclude PE. In a prospective 1-year evaluation, the Emergency Department at Brigham and Women's Hospital mandated obtaining a D-dimer ELISA in all 1106 patients suspected of PE. It served as an excellent screening test, with a sensitivity of 96.4% and negative predictive value of 99.6%.

Data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) indicate that, contrary to classic teaching, arterial blood gases lack diagnostic utility for PE1, even though the PO2 and PCO2 will often both decrease. Among patients suspected of PE, neither the room air arterial PO2 nor calculation of the alveolar-arterial oxygen gradient can reliably differentiate or triage patients who actually have PE at angiography.

Electrocardiogram Classic abnormalities include sinus tachycardia; new-onset atrial fibrillation or flutter; and an S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III (Chap. 210). Often, the QRS axis is greater than 90°. T-wave inversion in leads V1 to V4, perhaps the most frequent but least publicized change, reflects right ventricular strain.

NONINVASIVE IMAGING MODALITIES

Chest Roentgenography A normal or near-normal chest x-ray in a dyspneic patient suggests PE1. Well-established abnormalities include focal oligemia (Westermark's sign), a peripheral wedged-shaped density above the diaphragm (Hampton's hump), or an enlarged right descending pulmonary artery (Palla's sign).

Venous Ultrasonography Confirmed DVT2 is usually an adequate surrogate for PE1. Ultrasonography of the deep venous system relies upon loss of vein compressibility as the primary criterion for DVT. About one-half of patients with PE have no imaging evidence of DVT, probably because the clot has already embolized to the lung or is in the pelvic veins, where ultrasonography is usually inadequate. Therefore, the workup for PE should continue if there is high clinical suspicion, despite a normal ultrasound examination.

Chest CT Computed tomography (CT) of the chest with intravenous contrast (ordinarily, 100 mL administered at 3 to 4 mL/s via an antecubital vein) is superseding lung scanning (see below) as the principal imaging test for the diagnosis of PE1. Chest CT effectively diagnoses large, central PE1 (Fig. 244-1). New generation multislice scanners image the entire thorax with 1-mm thin sections during a single 12- to 15-s breath-hold and can detect peripherally located thrombi in fifth order branches. In patients without PE, the lung parenchymal images may establish alternative diagnoses not apparent on chest x-ray that explain the presenting symptoms and signs, such as pneumonia, emphysema, pulmonary fibrosis, pulmonary mass, or aortic pathology.

Lung Scanning (See also Chap. 235) Small particulate aggregates of albumin labeled with a gamma-emitting radionuclide are injected intravenously and are trapped in the pulmonary capillary bed. The perfusion scan defect indicates absent or decreased blood flow, possibly due to PE1. Ventilation scans, obtained with radiolabeled inhaled gases such as xenon or krypton, improve the specificity of the perfusion scan. Abnormal ventilation scans indicate abnormal nonventilated lung, thereby providing possible explanations for perfusion defects other than acute PE. A high probability scan for PE is defined as having two or more segmental perfusion defects in the presence of normal ventilation (Fig. 244-2).

The diagnosis of PE1 is very unlikely in patients with normal and near-normal scans but is about 90% certain in patients with high-probability scans. Unfortunately, most patients have nondiagnostic scans, and fewer than half of patients with angiographically confirmed PE have a high-probability scan. Importantly, as many as 40% of patients with high clinical suspicion for PE and "low-probability" scans do, in fact, have PE at angiography.

Magnetic Resonance (MR) (Contrast-Enhanced) MR pulmonary angiography utilizes gadolinium contrast agent, which unlike iodinated contrast agents used in CT3 angiography, is not nephrotoxic. The risk of a contrast reaction with gadolinium is very low, and no ionizing radiation is used. When compared with first-generation chest CT scanning, results are similar. MR also assesses right ventricular function, thus making it a promising single test for both diagnosis of PE1 and assessment of hemodynamic effect.

Echocardiography More than half of patients with PE1 will have normal echocardiograms Nevertheless, this imaging test helps with the rapid triage of extremely ill patients who may have PE. Bedside echocardiography can usually reliably differentiate among illnesses that have radically different treatment, including acute myocardial infarction, pericardial tamponade, dissection of the aorta, and PE complicated by right heart failure. McConnell's sign, i.e., right ventricular free wall hypokinesis with normal right ventricular apical motion, appears to be specific for PE. Detection of right ventricular dysfunction due to PE helps to stratify the risk, delineate the prognosis, and plan optimal management.

INVASIVE DIAGNOSTIC MODALITIES

Pulmonary Angiography Selective pulmonary angiography is the most specific examination available for establishing the definitive diagnosis of PE1 and can detect emboli as small as 1 to 2 mm. A definitive diagnosis of PE depends upon visualization of an intraluminal filling defect in more than one projection. Secondary signs of PE include abrupt occlusion ("cut-off") of vessels; segmental oligemia or avascularity; a prolonged arterial phase with slow filling; or tortuous, tapering peripheral vessels. Chest CT4 scanning is replacing diagnostic pulmonary angiography, because it is less invasive. In the current era of chest CT with contrast, pulmonary angiography is reserved for (1) patients with technically inadequate CT scans, (2) scans performed on older machines that cannot image fourth- and fifth-order pulmonary arteries, and (3) patients who will undergo interventions such as catheter embolectomy or catheter-directed thrombolysis.

Contrast Phlebography Venous ultrasonography has virtually replaced contrast phlebography, which is costly, uncomfortable, and occasionally results in contrast allergy or contrast-induced phlebitis.

INTEGRATED DIAGNOSTIC APPROACH

We advocate an integrated diagnostic approach to streamline the workup of PE1 (Fig. 244-3). This strategy combines the clinical likelihood of PE with the results of noninvasive testing, especially D-dimer ELISA5, venous ultrasonography, and chest CT6 or lung scanning to determine whether pulmonary angiography is warranted.

TREATMENT

Primary Therapy versus Secondary Prevention Primary therapy consists of clot dissolution with thrombolysis or removal of PE1 by embolectomy. Anticoagulation with heparin and warfarin or placement of an inferior vena caval filter constitutes secondary prevention of recurrent PE rather than primary therapy.

Risk Stratification Risk stratification is crucial in determining treatment strategy. The presence of hemodynamic instability, right ventricular dysfunction, or elevation of the troponin level due to right ventricular microinfarction can identify high-risk patients.

Primary therapy should be reserved for patients at high risk of an adverse clinical outcome. When right ventricular function remains normal in a hemodynamically stable patient, a good clinical outcome is highly likely with anticoagulation alone (Fig. 244-4).

Adjunctive Therapy Important adjunctive measures include pain relief (especially with nonsteroidal anti-inflammatory agents), supplemental oxygenation, and psychological support. Dobutamine — a ß-adrenergic agonist with positive inotropic and pulmonary vasodilating actions — may be effective in the treatment of right heart failure and cardiogenic shock. Volume loading should be undertaken cautiously because increased right ventricular dilatation can lead to even further reductions in left ventricular forward output.

Heparin Heparin binds to and accelerates the activity of antithrombin III, an enzyme that inhibits the coagulation factors thrombin (factor IIa), Xa, IXa, XIa, and XIIa. Heparin thus prevents additional thrombus formation and permits endogenous fibrinolytic mechanisms to lyse clot that has already formed. After 5 to 7 days of heparin, residual thrombus begins to stabilize in the endothelium of the vein or pulmonary artery. However, heparin does not directly dissolve thrombus that already exists.

MODIFIED CONSENSUS GUIDELINES FOR THE TREATMENT OF PULMONARY EMBOLISM FROM THE AMERICAN COLLEGE OF CHEST PHYSICIANS

1. Treat DVT7 or PE1 with therapeutic levels of unfractionated intravenous heparin, adjusted subcutaneous heparin, or low-molecular-weight heparin for at least 5 days, and overlap with oral anticoagulation for at least 4 to 5 days. Consider a longer course of heparin, approximately 10 days, for massive PE or severe iliofemoral DVT.

2. For most patients, heparin and oral anticoagulation can be started together and heparin discontinued on day 5 or 6 if the INR has been therapeutic for two consecutive days.

3. Treat patients with reversible or time-limited risk factors for at least 3 months. Patients with a first episode of idiopathic DVT8 should be treated indefinitely. A proven regimen is warfarin, target INR of 2.0 to 3.0 for 6 months, followed by low-intensity warfarin, target INR of 1.5 to 2.0.

4. The use of thrombolytic agents continues to be highly individualized, and clinicians should have some latitude in using these agents. Patients with hemodynamically unstable PE or massive iliofemoral thrombosis are the best candidates.

5. Inferior vena caval filter placement is recommended when there is a contraindication to or failure of anticoagulation, for chronic recurrent embolism with pulmonary hypertension, and with concurrent performance of surgical pulmonary embolectomy or pulmonary endarterectomy.

Modified from TM Hyers et al: Antithrombotic therapy for venous thromboembolic disease Chest 119:176S, 2001.

LOW-MOLECULAR-WEIGHT HEPARINS These fragments of unfractionated heparin exhibit less binding to plasma proteins and endothelial cells and consequently have greater bioavailability, a more predictable dose response, and a longer half-life than unfractionated heparin. No laboratory monitoring or dose adjustment is needed unless the patient is markedly obese or has renal insufficiency. Therefore, low-molecular-weight heparins, although more expensive, are far more convenient to use than unfractionated heparin. A meta-analysis of more than 3500 acute DVT9 patients showed that those treated with low-molecular-weight heparin had an overall 29% reduction in mortality and major bleeding compared with the unfractionated heparin group.

DOSING For unfractionated heparin, a typical intravenous bolus is 5000 to 10,000 units followed by a continuous infusion of 1000 to 1500 units/h. An activated partial thromboplastin time that is at least twice the control value should provide a therapeutic level of heparin. Nomograms based upon a patient's weight may assist in adjusting the dose of heparin. The most popular nomogram utilizes an initial bolus of 80 units/kg, followed by an initial infusion rate of 18 units/kg per hour.

Enoxaparin has received U.S. Food and Drug Administration (FDA) approval for both prophylaxis and treatment of patients who present primarily with symptomatic DVT10, with or without concomitant (but usually asymptomatic) PE1. The preferred dose is 1 mg/kg twice daily. An alternative back-up regimen for patients who can only receive one injection daily is 1.5 mg/kg daily. The FDA has approved dalteparin for prophylaxis but not for treatment of venous thromboembolism.

COMPLICATIONS The most important adverse effect of heparin is hemorrhage. For life-threatening or intracranial hemorrhage, protamine sulfate can be administered. Heparin-induced thrombocytopenia and osteopenia are far less common with low-molecular-weight heparins than with unfractionated heparin. Thrombosis due to heparin-induced thrombocytopenia should be managed with a direct thrombin inhibitor: argatroban for patients with renal insufficiency or hirudin for patients with hepatic failure. Heparin-associated elevations in transaminase levels occur commonly but are rarely associated with clinical toxicity.

Warfarin This vitamin K antagonist prevents ? carboxylation activation of coagulation factors II, VII, IX, and X. The full effect of warfarin often requires 5 days, even if the prothrombin time, used for monitoring, becomes elevated more rapidly. When warfarin is initiated during an active thrombotic state, the levels of protein C and S decline, thus creating a paradoxical thrombogenic potential. By overlapping either unfractionated or low-molecular-weight heparin and warfarin for 5 days, the early procoagulant effect of unopposed warfarin can be counteracted. Thus, heparin acts as a "bridge" until the full anticoagulant effect of warfarin is obtained.

DOSING In an average-sized adult, warfarin is usually initiated in a dose of 5 mg. Doses of 7.5 or 10 mg can be used in obese or large-framed young patients who are otherwise healthy. Patients who are malnourished or who have received prolonged courses of antibiotics are probably deficient in vitamin K and should receive smaller initial doses of warfarin, such as 2.5 mg. An uncommon genetic mutation delays the metabolism of warfarin, resulting in a very low dose requirement, 1 to 2 mg daily, to achieve a therapeutic affect. The prothrombin time is standardized with the INR, which assesses the anticoagulant effect of warfarin (Chap. 103). The target INR is usually 2.5, with a range of 2.0 to 3.0.

COMPLICATIONS As with heparin, bleeding is the most important and common complication associated with warfarin administration. Life-threatening bleeding can be treated with cryoprecipitate or fresh-frozen plasma (usually 2 units) to achieve immediate hemostasis. Recombinant factor VIIa is an effective, novel therapy for life-threatening bleeding in the setting of excessive warfarin. For less serious bleeding, or an excessively high INR in the absence of bleeding, vitamin K may be administered. Reversing excessive INRs by withholding warfarin and prescribing a low dose of oral vitamin K, such as 2.5 mg, will facilitate reestablishing a stable dose of warfarin.

Warfarin-induced skin necrosis is a rare complication that may be related to warfarin-induced reduction of protein C. It is usually associated with administration of a high initial dose of warfarin during an acute thrombotic state in which heparin is withheld.

During pregnancy, warfarin should be avoided if possible because of warfarin embryopathy, which is most common with exposure during the sixth through twelfth weeks of gestation. However, women can take warfarin postpartum and breast feed safely. Warfarin can also be administered safely during the second trimester.

DURATION OF ANTICOAGULATION Patients with PE1 following surgery or trauma ordinarily have a low rate of recurrence after 6 months of anticoagulation. In contrast, among patients with "idiopathic" PE, the recurrence rate is surprisingly high after cessation of anticoagulation. The PREVENT Trial establishes intensive anticoagulation with warfarin for 6 months, target INR of 2.0 to 3.0 followed by an indefinite duration of anticoagulation with low-intensity warfarin, target INR of 1.5 to 2.0.

Inferior Vena Caval Filters The two principal indications for insertion of an inferior vena caval filter are: (1) active bleeding that precludes anticoagulation, and (2) recurrent venous thrombosis despite intensive anticoagulation. Prevention of recurrent PE1 in patients with right heart failure who are not candidates for thrombolysis or prophylaxis of extremely high-risk patients are "softer" indications that are being utilized less frequently. The filter itself may fail by permitting the passage of small to medium-sized clots or because large thrombi embolize to the pulmonary arteries via collateral veins that develop. A more common complication is caval thrombosis with marked bilateral leg swelling. Paradoxically, by providing a nidus for clot formation, filters double the DVT11 rate over the ensuing 2 years following placement.

Thrombolysis Successful thrombolytic therapy rapidly reverses right heart failure and leads to a lower rate of death and recurrent PE1. Thrombolysis usually: (1) dissolves much of the anatomically obstructing pulmonary arterial thrombus; (2) prevents the continued release of serotonin and other neurohumoral factors that exacerbate pulmonary hypertension; and (3) dissolves much of the source of the thrombus in the pelvic or deep leg veins, thereby decreasing the likelihood of recurrent PE.

The preferred thrombolytic regimen is 100 mg of recombinant tissue plasminogen activator (tPA) administered as a continuous peripheral intravenous infusion over 2 h. Patients appear to respond to thrombolysis for up to 14 days after the PE1 has occurred. MAPPET-3 (Management Strategy and Prognosis of Pulmonary Embolism Trial) is the largest randomized trial of thrombolysis (using 100 mg of tPA plus anticoagulation versus anticoagulation alone); 247 patients were enrolled with hemodynamically stable PE. Escalation of therapy (including use of pressors or intubation) was necessary in 24% of those receiving anticoagulation alone compared with 12% of those receiving tPA.

Contraindications to thrombolysis include intracranial disease, recent surgery, or trauma. There is a 1 to 2% risk of intracranial hemorrhage. Careful screening of patients for contraindications to thrombolysis is the best way to minimize bleeding risk.

Embolectomy The risk of intracranial hemorrhage with thrombolysis has prompted reevaluation of surgical embolectomy for acute PE1. At Brigham and Women's Hospital, 29 patients with massive PE were operated on in 25 months, with an 89% survival rate. This high survival rate may be attributed to improved surgical technique, rapid diagnosis and triage, and careful patient selection. A possible alternative to open surgical embolectomy is catheter embolectomy.

Pulmonary Thromboendarterectomy Patients who develop chronic pulmonary hypertension due to prior PE1 may become severely dyspneic at rest or with minimal exertion. They should be considered for pulmonary thromboendarterectomy which, if successful, can markedly reduce and at times even cure pulmonary hypertension (Chap. 220).

PREVENTION

Prophylaxis against PE1 is of paramount importance because venous thromboembolism is difficult to detect and poses an excessive medical and economic burden. Mechanical and pharmacologic measures often succeed in preventing this complication (Table 244-3). Patients at high risk can receive a combination of mechanical and pharmacologic modalities. Graduated compression stockings and pneumatic compression devices may complement mini-dose unfractionated heparin (5000 units subcutaneously twice or preferably three times daily), low-molecular-weight heparin, a pentasaccharide or warfarin administration. Computerized reminder systems can increase the use of preventive care among these patients. Patients who have undergone total hip replacement, total knee replacement, or cancer surgery will benefit from extended pharmacologic prophylaxis for a total of 4 to 6 weeks, especially with low-molecular-weight heparin


End file.
